The identification of polymorphisms in the coding region of the apolipoprotein (a) gene - Association with earlier identified polymorphic sites and influence on the lipoprotein (a) concentration

Lipoprotein (a) [Lp(a)] is a quantitative genetic trait in human plasma and elevated levels represent a major inherited risk factor for the developmen t of atherosclerotic disease. In our search for sequence polymorphisms in t he coding region of the apolipoprotein(a) [apo(a)] gene that may affect the Lp(a) concentration, four new polymorphic sites were identified. These inc lude two coinciding polymorphisms with an allele frequency of 38% located a t amino acid positions 87 and 101 (Leu(87,101)-->Val) in the interkringle r egion of kringle IV (K.IV) type 7 and two polymorphisms located in K.IV typ e 7 (Arg(60)-->Ser) and in K.IV type 10 (Tyr(2)-->Phe) both with estimated allele frequencies of about 1%. The linkage between the newly identified K.IV type 7 Leu(87,101) --> Val po lymorphism and earlier described polymorphic sites in the non-coding and co ding regions of the apo(a) gene, its distribution over the apo(a) isoform s izes and its possible influence on the Lp(a) concentration was analysed in 201 healthy unrelated Caucasians. The earlier described polymorphic sites i ncluded in this study were the variable number of a TTTTA pentanucleotide r epeat (7-11 PNR) starting at -1231 bp, the -772 bp G/A polymorphism, the +9 3 bp C/T polymorphism and the +121 bp G/A polymorphism in the non-coding re gion, and the K.IV type 8 Thr(12)/Pro polymorphism and the K.IV type 10 Thr (66)/Met polymorphism in the coding region of the apo(a) gene. Linkage disequilibria were observed between the polymorphic sites in the 5' non-coding region and the sites in K.IV type 7 and 8 in the coding region of the apo(a) gene, confirming that the expansion of the variable number of K.IV type 2 repeats results from intrachromosomal recombinational events. The distribution over the apo(a) isoform sizes of the K.IV type 7 Val(87,10 1) subtype was not significantly different from that of the K.IV type 7 Leu (87,101) wild-type, suggesting a relative ancient mutational event. No infl uence of the K.IV type 7 Leu(87,101)-->Val polymorphism on the Lp(a) level was observed. In fact, of all the polymorphic sites studied, only the +121 A subtype could be associated with an increased, and the K.IV type 8 Pro(12 ) and the 10 PNR subtypes with a reduced, Lp(a) concentration corrected for apo(a) isoform size (p < 0.05).